T cell recognition of naturally expressed TCR V gene determinants represents an important regulatory mechanism for inhibiting T cell-mediated inflammatory responses and autoimmune diseases. In theory, anti-TCR response occurs during the formation of the T cell repertoire and involves T cell display of MHC-associated V gene epitopes. Thereafter, expansion of inflammatory T cells would lead to a coordinate activation of TCR-reactive Th2 cells that would eventually limit the Thl cell response and return the system to equilibrium. Our studies have demonstrated that vaccination of multiple sclerosis (MS) patients with TCR CDR2 peptides expressed by neuroantigen-specific Thl cells can rapidly boost anti-TCR Th2 responses in about half of the injected patients, with an associated decrease in response to the neuroantigen and a possible clinical benefit. However, a basic understanding of T-T network interactions is still lacking. In preliminary studies using the ELISPOT assay, the investigators observed that healthy donors had a substantial frequency (200-500 cells/million blood cells) of IL 10 producing Th2 cells specific for CDR2 peptides. In contrast, half of the MS patients had decreased responses (0-31 cells/million blood cells). Taken together, these data suggest that MS patients have a selective regulatory defect that might allow expansion of pathogenic T cells. The investigators' general hypothesis is that human anti-TCR reactive Th2 cells can regulate both target and bystander Thl cells by recognition of TCR determinants of the cognate V gene and release of inhibitory cytokines. The lack of TCR-specific Th2 cells in some MS patients could explain observed V gene bias by allowing selective expansion of Thl cells expressing unregulated V genes, including potentially pathogenic myelin-reactive T cells. The specific aims of this proposal will 1) define naturally processed and expressed TCR determinants recognized by regulatory Th2 cells, 2) investigate the mechanism by which TCR reactive T cells regulate target and bystander Thl cells, and 3) evaluate the degree and extent of the defective Th2 response to recombinant TCR proteins and peptides in MS patients and controls, and relate decreased anti-TCR response to oligoclonal expansions of activated Thl cells. This proposal represents an important first step to define the molecular basis for natural T-T network interactions, and the information obtained will be crucial for understanding how TCR peptide vaccination affects this basic regulatory mechanism in the context of a putative Thl-mediated inflammatory disease. Conceivably, successful vaccination with TCR peptides affects mainly those MS patients with defective anti-TCR T cell frequencies by boosting regulatory Th2 responses. The approach outlined in this proposal thus has the potential to define the set of TCR determinants needed to restore deficient regulatory responses in each patient.